Guidelines for the management of actinic keratoses
D. de Berker, J.M. McGregor* and B.R. Hughes on behalf of the British Association of Dermatologists Therapy Guidelines and Audit SubcommitteeBristol Dermatology Centre, Bristol Royal Infirmary, Bristol BS2 8HW, U.K.
*Department of Dermatology, St Bartholomew’s and the London NHS Trust, London E1 1BB, U.K. Portsmouth Dermatology Centre, St Mary’s Hospital, Milton Road, Portsmouth PO3 6AD, U.K.
Correspondence
David de Berker.
E-mail: david.deberker@ubht.swest.nhs.uk
Accepted for publication
21 May 2006
Key words
actinic keratosis, guidelines, treatment
Conflicts of interest
D. de B., none; J.M.M. has received an honorarium from 3M as an invited member of an advisory board for the treatment of actinic keratoses; B.R.H., none.
Members of the British Association of Dermatologists Therapy Guidelines and Audit Subcommittee are: A.D. Ormerod (Chairman), D.J. Eedy, D. Mitchell, F. Humphreys, J. Peters, R. Bull, H. Bell, M. Kouimtzi and S. Jones.
Summary
These guidelines stemmed from a consensus meeting held by the British Photo-biology Group (BPG) in 1999. Following this meeting one of the authors (J.M.M.) was invited to draw up guidelines for the management of actinic keratoses by the British Association of Dermatologists Therapy Guidelines and Audit Subcom-mittee. Relevant evidence was sought using the search terms ‘solar keratosis’ and ‘actinic keratosis’ in Medline from 1966 onwards. Additional and earlier litera-ture was reviewed on the basis of references within post-1966 publications. All articles of apparent relevance were reviewed independently of the nature of the publication. The quality of the evidence elicited has been indicated. The National Ambulatory Medical Care Survey (U.S.A.) was used for further data on topical chemotherapy. Papers were reviewed and discussed by the contributors to the BPG Workshop (see Acknowledgments). Recommendations are evidence based where possible. Strength of recommendation is coupled with quality of evidence. Strength of recommendation includes consideration of apparent cost-benefit and practical considerations. Quality of evidence reflects the nature of the trial struc-ture that provides data of efficacy.
Disclaimer
These guidelines have been prepared for dermatologists on behalf of the British Association of Dermatologists (BAD) and reflect the best data available at the time the report was pre-pared. Caution should be exercised in interpreting the data; the results of future studies may require alteration of the con-clusions or recommendations in this report. It may be neces-sary or even desirable to depart from the guidelines in the interests of specific patients and special circumstances. Just as adherence to the guidelines may not constitute defence against a claim of negligence, so deviation from them should not necessarily be deemed negligent.
Methodology
These guidelines stemmed from a consensus meeting held by the British Photobiology Group (BPG) in 1999. Following this meeting one of the authors (J.M.M.) was invited to draw up guidelines for the management of actinic keratoses (AKs) by the BAD Therapy Guidelines and Audit Subcommittee. Medline (1966–2004) was the main source of references for this
review. Relevant evidence was sought using the search terms ‘solar keratosis’ and ‘actinic keratosis’. Additional and earlier literature was reviewed on the basis of references within post-1966 publications. All articles of apparent relevance were reviewed independently of the nature of the publication. The National Ambulatory Medical Care Survey (U.S.A.) was used for further data on topical chemotherapy. Papers were reviewed and discussed by the contributors to the BPG Work-shop (see Acknowledgments).
Definition and introduction to the guideline
Actinic (syn. solar) keratoses are keratotic lesions occurring on chronically light-exposed adult skin. They represent focal areas of abnormal keratinocyte proliferation and differentiation that carry a low risk of progression to invasive squamous cell car-cinoma (SCC). A spectrum of histology is seen but the cardi-nal feature of an AK is epithelial dysplasia. This may be restricted to the basal layer or may extend to full-thickness atypia at which point differentiation from Bowen’s disease can be difficult. There is disorderly arrangement and maturation of epithelial cells. Multiple buds of epithelial cells may occur at
the membrane zone but no invasion is seen. Histological vari-ants of AK have been described, including hypertrophic, bow-enoid, lichbow-enoid, acantholytic and pigmented.
AKs are widely considered to be premalignant lesions with low individual potential for invasive malignancy and higher potential for spontaneous regression. They present as discrete, sometimes confluent, patches of erythema and scaling on pre-dominantly sun-exposed skin, usually in middle-aged and elderly individuals. They are often asymptomatic but may occasionally be sore or itch. Lesions may be single or multiple. The epidemiology, risk factors, disease associations and demo-graphics of the ‘at-risk’ population are all pertinent to patient
management. They are discussed together with the available treatment options.
Epidemiology
Evidence suggests that most AKs are the result of chronic expo-sure to ultraviolet (UV) radiation. They occur predominantly on chronically sun-exposed skin, such as that of the face and dorsa of hands, in fair-skinned individuals.1In addition, UVB-specific p53 mutations have been demonstrated in AKs, providing molecular evidence in support of a role for sunlight.2There is a high prevalence in those receiving chronic immunosuppression
Table 1 Factors determining choice of active therapy from six main alternatives. The scoring is based on the authors’ evaluation of efficacy, ease of use, morbidity and cost-benefit
Cryosurgery 5-FU Diclofenac Imiquimoda Curettage PDT Comments Main characteristic of AKs
Low number of AKs •••• •••• •• •• • •
High number of AKs ••• •••• ••• ••• • •••
Thin AKs ••• •••• ••• ••• • •• Thin lesions may not always
require treatment
Hypertrophic AKs •• • • • •••• • Histology may be required.
Formal excision may be preferred Isolated lesions failing to
respond to other therapies
•• • • • •••• • Histology may be required.
Formal excision may be preferred Confluent recalcitrant AKs,
failing other treatments
••• ••• • ••• • ••• Certain lesions within a resistant
field may require histological assessment
Location
Scalp, ears, nose, cheeks, forehead, perioral
•••• •••• ••• •••• ••• •••
Periorbital ••• • • • ••• ••• Topical therapies can be difficult
to use near mouth and eyes
Confluent scalp ••• •••• ••• •••• • •••• Pretreatment with 5% salicylic acid
ointment may improve outcome
Below the knee ••• • •• • •••• •••• Poor healing is a particular concern
at this site. All modalities can lead to ulceration. Treatment may be combined with advice on elevation and compression bandaging where possible
Back of hands •••• •••• •• • ••• ••• Courses of topical therapy may need
to be extended and pretreatment with 5% salicylic acid ointment may improve outcome Characteristics of patient (rating may be considered in context of clinical need indicated by characteristic of AK and location) Medically dependent
or senile
••• •• ••• • • ••• Morbidity of treatment may dictate
choice of modality
Self-reliant ••• •••• ••• •••• • • 5-FU may be repeated at sites of
relapse or new lesions in primary care
One-off treatment •••• •••• • •••• ••• •••
Lives far from hospital ••• •••• ••• •••• – – May favour treatment that allows
monitoring in primary care Part of continuous
management plan
•••• •••• ••• • • •••
5-FU, 5-fluorouracil; PDT, photodynamic therapy; AKs, actinic keratoses; ••••, good treatment; •••, fair treatment, ••, can be used depending on circumstances; •, rarely used in these circumstances.aImiquimod is not currently licensed for use in the treatment of AKs.
as organ transplant recipients.3 Other possible risk factors include exposure to arsenic4,5and chronic sun bed use.6–8
Incidence and prevalence
In Ireland and the U.K., 24%, 23% and 19% of individuals aged over 60 years were found to have at least one AK in studies from Galway, South Wales and Merseyside, respect-ively.9–11 There was a linear increase in the prevalence with age (from 60 to 80 years) in men but not in women, and the rate of new AKs was estimated to be 149 per 1000 person-years.10AKs were also present in 3Æ6% of men aged between 40 and 49 years.11
Natural history: spontaneous regression and malignant transformation
Studies indicate a high spontaneous regression rate in the order of 15–25% for AKs over a 1-year period,10,12and a low rate of malignant transformation, less than one in 1000 per annum.13 None the less, mathematical models derived from this study predict that for an individual with an average of 7Æ7 AKs, the probability of at least one transforming within a 10-year period is approximately 10%.14
When 918 adults (mean age 61 years) with AKs but no pre-vious history of skin cancer were followed prospectively for 5 years, the incidence rate for basal cell carcinoma (BCC) and SCC was estimated at 4106 and 3198 per 100 000 person-years, respectively, representing a substantial excess incidence compared with the general population.15 These data suggest that even though the risk of malignant transformation for any given AK is very low, the probability of an individual with AKs presenting subsequently with skin cancer is none the less high compared with the population at large.
Investigation and diagnosis
Patients with AKs may present to dermatologists in various cir-cumstances: they may be referred by the general practitioner (GP) because of diagnostic uncertainty or concern about malignant risk or for further management, and AKs may be detected incidental to referral for another problem, or detected during follow up of a skin cancer patient. Diagnosis is fre-quently made on clinical appearance alone but as the differen-tial diagnosis includes superficial BCC, Bowen’s disease, invasive SCC and even amelanotic melanoma, a skin biopsy may be indicated in selected cases where there is clinical doubt or suspicion of invasive malignancy.
Management
Many options are open to patients with AKs. The natural his-tory of individual lesions studied in the U.K. suggests that treatment is not universally required on the basis of prevent-ing progression into SCC.10 However, others feel that preven-tion of SCC is the main reason for therapy.16
Some AKs have histological features within the spectrum of in-situ skin cancer. They can also represent a cause of symp-toms and disfigurement which may be the main determinant of treatment choices. Clinical judgement should discern which lesions are more likely to represent a risk to the patient’s health, but where the likelihood is low, options include no therapy or palliation with emollient or keratolytic agent such as low-strength salicylic acid ointment.
Where active treatment is sought, many modalities of ther-apy are available (Table 1). Good-quality data on the outcome of these different therapies are available in only a few instances. Treatment of an individual lesion may have a thera-peutic effect on surrounding skin, with an effect on overall progression of actinic damage, but this potential benefit has not been quantified. Given the low morbidity and risk of the majority of AKs, the Strength of recommendation (see Appendix 1) made for treatments by the authors has an element of cost-benefit and risk-cost-benefit included. This is derived from clinical experience in addition to the published evidence.
No therapy (Strength of recommendation A, quality of evidence II-ii)
Harvey et al.10 reported in a study of 560 individuals from Wales that 21% of AKs resolved spontaneously over a 12-month period and none progressed into SCC. Marks et al.13 reported the evolution of AKs in an Australian cohort, where malignant transformation was quoted at 0Æ075–0Æ096% of AKs per year.
Topical therapies
• No therapy (A, II-ii) or emollient (A, I) is a reasonable option for mild AKs
• Sun block applied twice daily for 7 months may protect against development of AKs (A, I)
• 5-Fluorouracil cream used twice daily for 6 weeks is effect-ive for up to 12 months in clearance of the majority of AKs. Due to side-effects of soreness, less aggressive regimens are often used, which may be effective, but have not been fully evaluated (A, I)
• Diclofenac gel has moderate efficacy with low morbidity in mild AKs. There are few follow-up data to indicate the dur-ation of benefit (B, I)
• Imiquimod 5% cream is not licensed for AKs, but has been demonstrated to be effective over a 16-week course of treat-ment but only 8 weeks of follow up. By weight, it is 19 times the cost of 5-fluorouracil. They have similar side-effects (B, I)
Emollient (Strength of recommendation A, quality of evidence I)
There are no trials dedicated to the study of palliative therapy of AKs but emollient has been employed in the placebo arm
of a double-blind trial of masoprocol cream.17 Forty subjects were in the vehicle placebo group, with an average of 13Æ4 AKs each falling to 11Æ1 after 28 days of emollient twice a day. This represented improvement in the global evaluation score in 44% of subjects, with only 2Æ4% showing a deterior-ation. The vehicle limb of a randomized trial of diclofenac gel in hyaluronan vehicle described resolution of the target lesion in 44% of subjects using the vehicle after 60 days.18 Follow-up data are lacking and it is likely that the treatment is man-aging the clinical manifestations of mild AKs rather than reversing biological processes.
Sun block (Strength of recommendation A, quality of evidence I)
Sun block has a combined emollient and photoprotective effect. A randomized placebo-controlled trial of sun block with factor 17 protection applied twice daily to the face for 7 months showed sun block to be superior to emollient in terms of total number of AKs and new lesions at the end of the trial.19A single daily application of sun block (sun protec-tion factor 16) in Queensland, Australia, showed it to be superior to discretionary use of the same sun block over a 2-year period in the reduction of AKs.20A similar approach in the same setting also reduced the incidence of cutaneous SCCs.21
Salicylic acid ointment (Strength of recommendation A, quality of evidence III)
Salicylic acid ointment is sometimes used as a preliminary to topical 5-fluorouracil (5-FU) to remove overlying keratin. Fifty per cent salicylic acid in croton oil has been described as a treatment for AKs when used in combination with 20% tri-chloroacetic acid (TCA) and pretreatment with topical tretino-in as a serial regimen for facial peel.22 Acting primarily as an emollient for mild keratoses17,18(see above under Emollient), it may provide a small additional benefit based on the kerato-lytic effect. Thus 2% salicylic acid ointment BP may be used for its combined emollient and mild keratolytic effects, either alone or as pretreatment for topical 5-FU.
5-Fluorouracil (Strength of recommendation A, quality of evidence I)
The majority of the data on topical therapies relates to 5-FU. A wide range of open trials, dose-ranging studies and manipu-lations of the vehicle has been reported over the last 35 years, as well as two randomized controlled trials (RCTs), confirm-ing efficacy. 5-FU works by the inhibition of thymidylate syn-thetase, which is needed for DNA synthesis. It may also interfere with the formation and function of RNA.23
Nine of the trials were controlled, where a right/left com-parison (n¼ 6) was the most common design, but only five were randomized. Numbers in the studies were generally small, with a mean of 26 patients per trial and fewer than 15
patients in 50% of trials. Minimum follow up was 12 months or more in only two studies. Many open studies appeared to demonstrate the efficacy of 5-FU in a range of potencies and different vehicles in the treatment of AKs when used on the face twice daily for 3 weeks. Only two trials studied the use of 5-FU in the currently available formulation of a 5% cream in a well-constructed, controlled manner.24,25 Kurwa et al.25 examined the lesional area of AKs on the back of the hands before and after treatment with 5% 5-FU cream twice daily for 3 weeks in a randomized right/left comparison with a sin-gle treatment with photodynamic therapy (PDT). Of the 14 patients evaluable at 6 months, there was a mean reduction in lesional area of 70% (5-FU) and 73% (PDT), with no statisti-cally significant difference between them. Open studies have suggested that this regimen is not sufficiently long for effect-ive treatment of AKs on the hands,26but is adequate for those on the face.24 Witheiler et al.24 used 5% 5-FU cream on the face as control in a right/left comparison with a single appli-cation of Jessner’s solution (14% lactic acid, 14% salicylic acid, 14% resorcinol in ethanol) followed by a 35% TCA peel. There was a mean reduction in AKs on both sides of the face from 18 to four (78% reduction with 5-FU and 79% reduc-tion with TCA). This benefit was sustained for 12 months. The third follow up at 32 months demonstrated that the num-ber of AKs had risen again to 10 (5-FU) and 15 (TCA) in the eight evaluable patients. These differences were not statistically significant.
The results of using the same formulation of 5-FU less fre-quently, but for prolonged periods, are conflicting. An open trial of 10 patients reported clearance of 96% of AKs after a mean of 6Æ7 weeks applying treatment twice daily, once or twice per week.27 Six patients were followed for 9 months and showed an 86% clearance rate that was maintained. Epstein28followed this study with a similar protocol and sam-ple size, except that evaluation was done by dermatologists given a series of photographs and blinded as to the sequence. Eight of 13 patients failed to show any improvement, with the conclusion that pulsing 5-FU over a period of < 10 weeks is not effective. The small numbers of patients in both these studies leave the matter unresolved. Five per cent 5-FU cream was used alone or in combination with topical tretinoin to the back of the hands at night for 3 months in a blinded right/left comparison with a 3-month follow-up period.29 Both sides produced a reduction of > 70% in AKs, with a statistically sig-nificant advantage to the side treated with additional tretinoin.
Imiquimod 5% cream (Strength of recommendation B, quality of evidence I)
Imiquimod 5% cream is a topical immune response modifier. A small early RCT against vehicle placebo30 demonstrated clearance rates of 84% when used up to three times per week for 12 weeks. There have been two RCTs31,32 with regimens of three times per week for 16 weeks and follow up 8 weeks later. These have classified responses in terms of complete or partial (> 75%) clinical clearance or histological clearance.
Results indicated 47% of patients with complete clearance (vs. 7Æ2% with placebo) increasing to 64% when adding those with partial clearance (vs. 13Æ6% with placebo).31Histological responses were 57% (vs. 2Æ2% for placebo) and 72% (vs. 4Æ3% for placebo) for the same categories.32 The side-effects are similar to 5-FU with severe erythema (30Æ6%), scabbing and crusting (29Æ9%) and erosions or ulceration (10Æ2%).32 The extent of side-effects is not wholly predictable, with some patients manifesting an extreme reaction and others very little. The clinical response is largely in proportion to the side-effects and those terminating treatment early due to extreme soreness may still get a good response. There are limited long-term data on relapse after treatment. The product is not cur-rently licensed for this indication and imiquimod is more expensive than 5-FU, gram for gram, by a factor of 19.33
Diclofenac gel (Strength of recommendation B, quality of evidence I)
There are two vehicle-controlled studies of 3% diclofenac in a 2Æ5% hyaluronic gel in the treatment of mild AKs. In the first, patients were treated for a mean of 60 days, with a resolution of 70% of target lesions in the treatment group in comparison with 44% in those using the vehicle.18 In the second study treatment was for 90 days, with 50% of those using active treatment achieving a target lesion number score of zero, vs. 20% of those treated with vehicle alone (P < 0Æ001).34 Assess-ment was limited to 30 days post-treatAssess-ment in both studies. These data provide indication of moderate efficacy with low morbidity in mild AKs. Treatment was well tolerated and side-effects were mainly pruritus (41% estimated after 30 days of treatment) and rash (40% estimated after 60 days).18
Tretinoin cream (Strength of recommendation B, quality of evidence I)
Topical tretinoin cream has been studied at different concen-trations. There is a dose response; Bollag and Ott35 reported complete clearance of AKs in 55% of subjects treated with 0Æ3% ointment vs. 35% of subjects with the same response when using 0Æ1%. Misiewicz et al.36 undertook a right/left comparison of tretinoin cream with arotinoid methyl sulphone on the face, revealing a reduction of AKs on the tretinoin-treated skin by 30Æ3% (P < 0Æ01) after twice-daily use for 16 weeks. At between 3 and 9 weeks there was a deterioration of clinical appearance to below baseline before benefit was seen. This reflects the potential benefit from currently available formulations of tretinoin. In a multicentre open trial, pub-lished in nonpeer-reviewed literature, there was a reduction of facial AKs from a mean of 11Æ2 to 8Æ9 (11% reduction) after 6 months’ use of 0Æ05% once or twice daily (P¼ 0Æ001). This changed to a reduction by 47% after 15 months’ use (P¼ 0Æ001).37These figures do not illustrate a significant advantage over emollient and sun block. The product is licensed for photodamage in the U.K., but not specifically for the treat-ment of AKs.
Masoprocol cream (Strength of recommendation C, quality of evidence I)
A single RCT for masoprocol17 suggested that this reduced AKs to 71% of the baseline number after a 28-day course of therapy. There was only a 1-month follow-up period. The product is not available in the U.K.
In conclusion, there is good evidence that 5% 5-FU cream used twice daily for 3 weeks is effective at reducing AKs on the face and back of hands by about 70% for up to 12 months. There is insufficient RCT evidence to support or refute the efficacy of alternative regimens and formulations, although one RCT suggests that a single night-time application for 3 months for AKs on the back of the hands is effective.29 Imiquimod has been more rigorously assessed with modern RCT design and may produce a similar pattern of side-effects and response to 5-FU. Diclofenac gel is a relatively mild agent that reduces the AK count but there are no follow-up data beyond 1 month. Topical tretinoin has some efficacy on the face, with partial clearance of AKs, but may need to be used for up to a year at a time to optimize benefit. Sun block, emollient and 2% salicylic acid ointment BP may reduce the AK count by a similar amount.
Other treatments
• Cryosurgery is effective for up to 75% of lesions in trials comparing it with photodynamic therapy. It may be partic-ularly superior for thicker lesions, but may leave scars (A, I)
• Photodynamic therapy is effective in up to 91% of AKs in trials comparing it with cryotherapy, with consistently good cosmetic result. It may be particularly good for superficial and confluent AKs, but is likely to be more expensive than most other therapies. It is of particular value where AKs are numerous or when located at sites of poor healing such as the lower leg (B, I)
• There are no studies of curettage or excisional surgery, but both are of value in determining the exact histological nat-ure of proliferative or atypical AKs unresponsive to other therapies, where invasive squamous cell carcinoma is possible
Surgery
There are no trials of surgical therapy for AKs. The nature of the pathology makes it likely that a surgical procedure able to remove an area of diseased skin represents an effective ther-apy. It is unlikely that this would be a first line of treatment unless there was diagnostic uncertainty. A curettage specimen may make it difficult to determine whether a lesion has an element of dermal invasion. In some instances a deep shave or formal excision with histological examination might be pre-ferred. If curettage is used for a hyperkeratotic AK, it may be warranted to employ two or three cycles of therapy. This will
ensure that if the histology is that of invasive SCC, or if it is equivocal, the curettage is likely to still represent adequate treatment. Exceptions would be where the size, histological type or location of an SCC would make curettage an unaccept-able treatment.38
In the U.S.A., surgical therapies, including electrodesicca-tion, are the preferred treatment of AKs provided by dermato-logists according to medical insurance data, where 75% are treated by ‘either local excision or destruction of lesion or tissue’.39
Cryosurgery (Strength of recommendation A, quality of evidence I)
A randomized study comparing cryosurgery with PDT in 193 patients indicated an overall 75% complete response rate for cryosurgery in contrast to 69% in those treated with PDT at 3 months.40 The differential success of the two therapies was more marked for thick lesions, with 69% showing complete response to cryosurgery vs. 52% to PDT. A double freeze– thaw cycle was used in this study in contrast to a single cycle which, when used in a different study, yielded a 68% response.41
Extensive cryosurgery over large areas has been referred to as cryopeeling and can be used for treating fields of AKs and background damage.42 Cryosurgery has been described in combination with topical 5-FU, where the duration of treat-ment and consequent side-effects of both modalities could be reduced while maintaining efficacy.43 No data were pre-sented to support this method. Cryosurgery is a flexible ther-apy that requires skill in administration. With larger doses it is likely to result in loss of pigment and scarring. Patient counselling is important concerning short- and long-term side-effects.
Photodynamic therapy (Strength of recommendation B, quality of evidence I)
PDT requires a dedicated light source in combination with the application of a photosensitizing cream. Photosensitizing agents include 5-aminolaevulinic acid (5-ALA) and a methyl ester of 5-ALA, 5-methylaminolaevulinate. The BPG pub-lished guidelines for the use of PDT in 2002,44 and conclu-ded that optimal irradiance, wavelength and dose for the treatment of AKs have yet to be established. For most situa-tions, superficial crust or keratin is first removed with light curettage and the photosensitizing cream then applied under occlusion for 3 h prior to irradiation. Treatment can be painful but the BPG guidelines44 describe the treatment as intrinsically safe.
Response rates to two cycles of PDT mainly on the scalp and face range from 69% to 91% in three randomized tri-als.40,41,45Studies had a 340,45to 441month follow-up period. In two studies where comparison was made with cryotherapy, one showed a higher clearance rate for cryotherapy (69% PDT vs. 75% cryotherapy)40and one showed a lower clearance rate
(91% PDT vs. 68% cryotherapy).41 Cryotherapy appeared to be superior for thicker lesions (PDT response 52Æ2% vs. cryo-therapy 69%) and lesions of the face and scalp (PDT response 75Æ8% vs. cryotherapy 91Æ7%). Local adverse reactions were reported by 44% of those receiving PDT and 26% of those given cryotherapy, although the cosmetic outcome in all stud-ies was consistently rated higher by patients for PDT (98%) than for cryotherapy (91%).40
A right/left comparison of AK treatment on the back of the hands by PDT and 5-FU showed a similar response to both therapies,25 clearing 73% and 70%, respectively. Responses remained similar at 6 months.
The cost-effectiveness of PDT is not established but its use is likely to be limited by the cost of the photosensitizing cream.
Laser, chemical peels and dermabrasion (Strength of recommendation C, quality of evidence III)
In principle, carbon dioxide laser or other destructive energy sources should be able to treat AKs.46 Chemical peels and dermabrasion should have a similar effect, where skin is des-troyed to a controlled depth. Spira et al.47 reported a poorly controlled comparison of AKs of the face treated with a phe-nolic peel, dermabrasion or topical 5-FU. All therapies worked initially, but patients developed further AKs within a month of treatment with phenolic peel, within 6 months of derm-abrasion and some time after 6 months following 5-FU. The nonblinded right/left comparison by Witheiler et al.24 of a 35% TCA peel and 5-FU on the face suggested that they were of similar efficacy, with improvement sustained up to 12 months, waning considerably by 32 months. TCA can be combined with 70% glycolic acid48or with manual dermabra-sion with silicon carbide sandpaper.49
In an open study of facial dermabrasion alone, 22 of 23 subjects (96%) remained free of AKs at 1 year and the mean period to development of a further AK was 4Æ5 years.50 Treat-ment of scalp actinic damage and keratoses with dermabrasion has been reported as effective.51
Systemic retinoids (Strength of recommendation B, quality of evidence I)
Systemic retinoids have been assessed for their potential role in suppression or treatment of multiple AKs. Early studies employed etretinate and demonstrated in double-blind cross-over trials the efficacy of this drug.52 Anecdotal evidence over the last 20 years suggests that there can be some considerable morbidity employing this treatment. In addition, there may be a rebound effect once the systemic therapy is stopped. How-ever, these effects were not observed at 4 months follow up in the one available report on this subject.53
Use of systemic retinoid may be justified in very high-risk patients, such as organ transplant recipients, where there is a presumed increased risk of progression from AK to SCC.54 Low-dose acitretin is currently given as a treatment option in
‘European best practice guidelines’ for renal transplant patients with multiple dysplastic skin lesions.55
Site-specific treatments
The data from available treatments indicate that some treat-ments are more adaptable than others and that morbidity var-ies with location. The balance of issues determined by location, characteristics of the AKs and nature of the patient are summarized in Table 1. The scoring is based on the authors’ evaluation of efficacy, ease of use, morbidity and cost-benefit.
Other considerations
Should actinic keratoses be treated?
There is inadequate evidence to justify treatment of all AKs to try to prevent malignant change. Treatment should be consid-ered on an individual basis according to signs, symptoms and history. There will be instances where excision is undertaken for diagnostic purposes.
Overall, the data comparing individual treatments are not good enough to justify making a single recommendation. Decisions for an individual patient will be based on the clin-ical presentation, the efficacy, morbidity, availability and cost of relevant treatments and patient preference.
However, treatment of small numbers of AKs with cryo-therapy is currently widely practised by dermatologists, while more extensive AKs are commonly treated with 5-FU. Due to expense and inconvenience PDT is probably best reserved for patients with extensive AKs that cannot be controlled with other therapies.
Is there a role for prevention and what works?
AKs are a marker for sun damage and therefore are an indica-tion to increase sun-avoidance measures. There is some evi-dence that regular use of sunscreen reduces the number of AKs19,20and the risk of SCC.21
Should patients with actinic keratoses have follow up? There are no data concerning the benefit of follow up in patients with AKs. Patients and their carers should be educated regarding changes that suggest malignancy. Those at high risk of nonmelanoma skin cancer, e.g. organ transplant recipients, may warrant follow up; the presence of numerous AKs is an indicator of this risk.
Are there high-risk groups and is their management different?
Patients with multiple and confluent AKs are likely to be at higher risk of nonmelanoma skin cancer, particularly patients with organ transplants who are estimated to have 50–100
times the risk of an age- and sex-matched control popula-tion.56,57 Anecdotal and limited trial data suggest that treat-ments for AKs in transplant patients are less effective than in the general population,58 perhaps because AKs are more pro-liferative and hyperkeratotic in this group, or because new lesions rapidly appear in the treated site. One study in trans-plant recipients failed to demonstrate a reduction in the devel-opment of subsequent skin cancers in those areas of skin previously treated for AKs with PDT.57
Cost-benefit of treatment
Most AKs result in few or no symptoms and are not danger-ous. Where there is a wide range of treatments it is necessary to balance the benefits of treatment against side-effects. In many health care systems this calculation will have some ele-ment of cost-benefit, where the cost is to the state and the indication must justify the expense. These guidelines are not able to give details on the complex matter of cost-benefit, but it is apparent that some treatments are considerably more expensive than others. Where outcomes are comparable and morbidity of treatment tolerable, we have tended to give a higher strength of recommendation to the cheaper treatment or one that is more easily used in primary care.
Summary of recommendations
AKs represent a spectrum of clinical complaint and pathology. Most patients can be diagnosed and managed in primary care. In many instances, management may entail little or no medical treatment other than advice on sun avoidance and self-monitor-ing. Where there is clinical concern or the patient specifically wants treatment, cryosurgery or one of the many topical therap-ies can be employed taking into consideration the specifics of the situation. If there is diagnostic concern or failure to respond to first-line treatment, a histological specimen, such as obtained at curettage with cautery or formal excision, may be both diag-nostic and curative. Where AKs are multiple or confluent, at sites of poor healing or with poor response to standard therap-ies, PDT may be helpful. Such patients may also warrant long-term follow up for the associated increased risk of nonmel-anoma skin cancer.
Audit points
AKs are a biological marker of sun damage and hence patients with AKs are at a greater risk of skin cancer than those with no AKs. Patients with AKs need to be educated on self-monit-oring and the need to seek a medical opinion if they detect new lesions or changes in old lesions on their skin.
• Evidence that the patient was provided with information about AKs and sun damage
• Evidence that the patient is adequately informed concerning the nature of any treatment when given
• Evidence that the GP is provided with advice concerning how to evaluate and manage further AKs when they develop
• Evidence that high-risk patients and their GPs are aware of their status. This includes organ transplant recipients, those with multiple large AKs or previous SCCs. Such patients need a low threshold of referral for lesions of an actinic nature or unclear diagnosis.
Acknowledgments
Contributions towards this were made by the British Photo-biology Group, London, 1999: Dan Creamer, Jane McGregor, David de Berker, Colin Morton, David Bilsland, Kevin McKenna, Helene du Peloux-Menage´ and Charlotte Proby.
References
1 Freeman RG. Carcinogenic effect of solar radiation and prevention measures. Cancer 1968; 21:11114–20.
2 Zeigler A, Jonason AS, Leffell DJ et al. Sunburn and p53 in the onset of skin cancer. Nature 1994; 372:773–6.
3 Barr BB, Benton EC, McLaren K et al. Papillomavirus infection and skin cancer in renal allograft recipients. Lancet 1989; ii:224–5. 4 Baudouin C, Charveron M, Tarroux R, Gall Y. Environmental
pol-lutants and skin cancer. Cell Biol Toxicol 2002; 18:341–8.
5 Wong ST, Chan HL, Teo SK. The spectrum of cutaneous and inter-nal malignancies in chronic arsenic toxicity. Singapore Med J 1998; 39:171–3.
6 Norris JF. Sun-screens, suntans and skin cancer. Local councils should remove sunbeds from leisure centres. BMJ 1996; 313:941–2. 7 Bajdik CD, Gallagher RP, Astrakianakis G et al. Non-solar ultraviolet
radiation and the risk of basal and squamous cell skin cancer. Br J Cancer 1996; 73:1612–14.
8 Roest MA, Keane FM, Agnew K et al. Multiple squamous cell carci-nomas following excess sunbed use. J R Soc Med 2001; 94:636–7. 9 O’Beirn SFO, Judge P, Maccon CF, Martin CF. Skin cancer in
County Galway, Ireland. In: Proceedings of the Sixth National Cancer Con-ference, sponsored by the American Cancer Society Inc. and the National Cancer Institute, September 1968. Philadelphia: Lippin-cott, 1970: 489–500.
10 Harvey I, Frankel S, Marks R et al. Non-melanoma skin cancer and solar keratoses. 1. Methods and descriptive results of the South Wales skin cancer study. Br J Cancer 1996; 74:1302–7.
11 Memon AA, Tomenson JA, Bothwell J, Friedmann PS. Prevalence of solar damage and actinic keratosis in a Merseyside population. Br J Dermatol 2000; 142:1154–9.
12 Marks R, Foley P, Goodman G et al. Spontaneous remission of solar keratoses: the case for conservative management. Br J Dermatol 1986; 155:649–55.
13 Marks R, Rennie G, Selwood TS. Malignant transformation of solar keratoses to squamous cell carcinoma. Lancet 1988; i:795–7. 14 Dodson JM, DeSpain J, Hewett JE, Clark DP. Malignant potential of
actinic keratoses and the controversy over treatment. Arch Dermatol 1991; 127:1029–31.
15 Foote JA, Harris RB, Giuliano AR et al. Predictors for cutaneous basal- and squamous-cell carcinoma among actinically damaged adults. Int J Cancer 2001; 95:7–11.
16 Callen JP, Bickers DR, Moy RL. Actinic keratoses. J Am Acad Dermatol 1997; 36:650–3.
17 Olsen EA, Abernathy L, Kulp-Shorten C et al. A double blind, vehi-cle controlled study evaluating masoprocol cream in the treatment of actinic keratoses of the head and neck. J Am Acad Dermatol 1991; 24:738–43.
18 Rivers JK, Arlette J, Shear N et al. Topical treatment of actinic kera-toses with 3Æ0% diclofenac in 2Æ5% hyaluronan gel. Br J Dermatol 2002; 146:94–100.
19 Thompson SC, Jolley D, Marks R. Reduction of solar keratoses by regular sunscreen use. N Engl J Med 1993; 329:1147–51.
20 Darlington S, Williams G, Neale R et al. A randomized controlled trial to assess sunscreen application and beta carotene supplementa-tion in the prevensupplementa-tion of solar keratoses. Arch Dermatol 2003; 139:451–5.
21 Green A, Williams G, Neale R et al. Daily sunscreen application and betacarotene supplementation in prevention of basal-cell and squa-mous-cell carcinomas of the skin: a randomised controlled trial. Lancet 1999; 354:723–9.
22 Swinehart JM. Salicylic acid ointment peeling of the hands and forearms. Effective nonsurgical removal of pigmented lesions and actinic damage. J Dermatol Surg Oncol 1992; 18:495–8.
23 Eaglstein WH, Weinstein GD, Frost P. Fluorouracil: mechanism of action in human skin and actinic keratoses. Arch Dermatol 1970; 101:132–9.
24 Witheiler DD, Lawrence N, Cox SE et al. Long-term efficacy and safety of Jessner’s solution and 35% trichloroacetic acid vs. 5% fluorouracil in the treatment of widespread facial actinic keratoses. Dermatol Surg 1997; 23:191–6.
25 Kurwa HA, Yong Gee SA, Seed P et al. A randomized paired com-parison of photodynamic therapy and topical 5-fluorouracil in the treatment of actinic keratoses. J Am Acad Dermatol 1999; 41:414–18. 26 Robinson TA, Kligman AM. Treatment of solar keratoses of the
extremities with retinoic acid and 5-fluorouracil. Br J Dermatol 1975; 92:703–6.
27 Pearlman DL. Weekly pulse dosing: effective and comfortable top-ical 5-fluorouracil treatment of multiple facial actinic keratoses. J Am Acad Dermatol 1991; 25:665–7.
28 Epstein E. Does intermittent ‘pulse’ topical 5-fluorouracil therapy allow destruction of actinic keratoses without significant inflamma-tion? J Am Acad Dermatol 1998; 38:77–80.
29 Bercovitch L. Topical chemotherapy of actinic keratoses of the upper extremity with tretinoin and 5-fluorouracil: a double-blind controlled study. Br J Dermatol 1987; 116:549–52.
30 Stockfleth E, Meyer T, Benninghoff B et al. A randomized, double-blind, vehicle-controlled study to assess 5% imiquimod cream for the treatment of multiple actinic keratoses. Arch Dermatol 2002; 138:1498–502.
31 Korman N, Moy R, Ling M et al. Dosing with 5% imiquimod cream 3 times per week for the treatment of actinic keratosis: results of two phase 3, randomized, double-blind, parallel-group, vehicle-controlled trials. Arch Dermatol 2005; 141:467–73.
32 Szeimies RM, Gerritsen MJ, Gupta G et al. Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, rand-omized, double-blind, vehicle-controlled, clinical trial with histol-ogy. J Am Acad Dermatol 2004; 51:547–55.
33 Stockfleth E, Christophers E, Benninghoff B, Sterry W. Low inci-dence of new actinic keratoses after topical 5% imiquimod cream treatment: a long-term follow-up study. Arch Dermatol 2004; 140:1542 [Letter].
34 Wolf JR, Taylor JR, Tschen E. Topical 3% diclofenac in 2Æ5% hya-luronan gel in the treatment of actinic keratoses. Int J Dermatol 2001; 40:709–13.
35 Bollag W, Ott F. Retinoic acid: topical treatment of senile or actinic keratoses and basal cell carcinomas. Agents Actions 1970; 1:172–5. 36 Misiewicz J, Sendagorta E, Golebiowska A et al. Topical treatment
of multiple actinic keratoses of the face with arotinoid methyl sulf-one cream vs. tretinoin cream: a double blind comparative study. J Am Acad Dermatol 1991; 24:448–51.
37 Kligman AL, Thorne EG. Topical therapy of actinic keratoses with tretinoin. In: Retinoids in Cutaneous Malignancy (Marks R, ed.), Oxford: Blackwell Scientific Publications, 1991; 66–73.
38 Motley R, Kersey P, Lawrence C, on behalf of the British Associ-ation of Dermatologists, the British AssociAssoci-ation of Plastic Surgeons & the Faculty of Clinical Oncology of the Royal College of Radiolo-gists. Multiprofessional guidelines for the management of the patient with primary cutaneous squamous cell carcinoma. Br J Dermatol 2002; 146:18–25.
39 Feldman SR, Fleischer AB, Williford PM, Jorrizzo JL. Destructive procedures are the standard of care for treatment of actinic keratoses. J Am Acad Dermatol 1999; 40:43–7.
40 Szeimies RM, Karrer S, Radakovic-Fijan S et al. Photodynamic ther-apy using topical methyl 5-aminolevulinate compared with cryo-therapy for actinic keratosis: a prospective, randomized study. J Am Acad Dermatol 2002; 47:258–62.
41 Freeman M, Vinciullo C, Francis D et al. A comparison of photo-dynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. Dermatolog Treat 2003; 14:99–106. 42 Chiarello SE. Cryopeeling (extensive cryosurgery) for treatment of
actinic keratoses: an update and comparison. Dermatol Surg 2000; 26:728–32.
43 Abadir DM. Combination of topical 5-fluorouracil with cryotherapy for treatment of actinic keratoses. J Dermatol Surg Oncol 1983; 9:403– 4.
44 Morton CA, Brown SB, Collins S et al. Guidelines for topical photo-dynamic therapy: report of a workshop of the British Photoderma-tology Group. Br J Dermatol 2002; 146:552–67.
45 Pariser DM, Lowe NJ, Stewart DM et al. Photodynamic therapy with topical methyl aminolevulinate for actinic keratosis: results of a prospective randomized multicenter trial. J Am Acad Dermatol 2003; 48:227–32.
46 Trimas SJ, Ellis DA, Metz RD. The carbon dioxide laser. An alter-native for the treatment of actinically damaged skin. Dermatol Surg 1997; 23:885–9.
47 Spira M, Freeman R, Arfai P et al. Clinical comparison of chemical peeling, dermabrasion, and 5-FU for senile keratoses. J Plast Reconstr Surg 1970; 46:61–6.
48 Tse Y, Ostad A, Lee HS et al. A clinical and histologic evaluation of two medium-depth peels. Glycolic acid vs. Jessner’s trichloroacetic acid. Dermatol Surg 1996; 22:781–6.
49 Cooley JE, Casey DL, Kauffman CL. Manual resurfacing and trichloroacetic acid for the treatment of patients with widespread actinic damage. Clinical and histologic observations. Dermatol Surg 1997; 23:373–9.
50 Coleman WP 3rd, Yarborough JM, Mandy SH. Dermabrasion for prophylaxis and treatment of actinic keratoses. Dermatol Surg 1996; 22:17–21.
51 Winton GB, Salasche SJ. Dermabrasion of the scalp as a treatment for actinic damage. J Am Acad Dermatol 1986; 14:661–8.
52 Moriarty M, Dunn J, Darragh A et al. Etretinate in treatment of acti-nic keratosis. A double-blind crossover study. Lancet 1982; i:364–5. 53 Watson AB. Preventative effect of etretinate therapy on multiple
actinic keratoses. Cancer Detect Prev 1986; 9:161–5.
54 McNamara IR, Muir J, Galbraith AJ. Acitretin for prophylaxis of cutaneous malignancies after cardiac transplantation. J Heart Lung Transplant 2002; 21:1201–5.
55 EBPG Expert Group on Renal Transplantation. European best prac-tice guidelines for renal transplantation. Section IV. Long-term
management of the transplant recipient. IV.6.2. Cancer risk after renal transplantation. Skin cancers: prevention and treatment. Nephrol Dial Transplant 2002; 17 (Suppl. 4):31–6.
56 Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplan-tation. N Engl J Med 2003; 348:1681–91.
57 de Graaf Y, Kennedy C, Wolterbeek R et al. Photodynamic therapy does not prevent cutaneous squamous cell carcinoma in organ transplant recipients: results of a randomised-controlled trial. J Invest Dermatol 2006; 126:569–74.
58 Dragieva G, Hafner J, Dummer R et al. Topical photodynamic ther-apy in the treatment of actinic keratoses and Bowen’s disease in transplant recipients. Transplantation 2004; 77:115–21.
59 Ormerod AD. Recommendations in British Association of Derma-tologists guidelines. Br J Dermatol 2005; 153:477–8.
Appendix 1
Strength of recommendations and quality of evidencea
Strength of recommendations
A There is good evidence to support the use of the procedure
B There is fair evidence to support the use of the procedure
C There is poor evidence to support the use of the procedure
D There is fair evidence to support the rejection of the use of the procedure
E There is good evidence to support the rejection of the use of the procedure
Quality of evidence
I Evidence obtained from at least one properly designed, randomized controlled trial II-i Evidence obtained from well-designed
controlled trials without randomization II-ii Evidence obtained from well-designed cohort
or case–control analytical studies, preferably from more than one centre or research group II-iii Evidence obtained from multiple time series
with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin treatment in the 1940s) could also be regarded as this type of evidence III Opinions of respected authorities based on
clinical experience, descriptive studies or reports of expert committees
IV Evidence inadequate owing to problems of methodology (e.g. sample size, or length of comprehensiveness of follow up, or conflicts in evidence)
aA new system of evidence grading and recommendations has been adopted for new guidelines,59but these were introduced after the inception of this guideline.
